Vimentin is required for tumor progression and metastasis in a mouse model of non-small cell lung cancer.

Vimentin is highly expressed in metastatic cancers, and its expression correlates with poor patient prognoses. However, no causal in vivo studies linking vimentin and non-small cell lung cancer (NSCLC) progression existed until now. We use three complementary in vivo models to show that vimentin is required for the progression of NSCLC. First, we crossed LSL-KrasG12D; Tp53fl/fl mice (KPV+/+) with vimentin knockout mice (KPV-/-) to demonstrate that KPV-/- mice have attenuated tumor growth and improved survival compared with KPV+/+ mice. Next, we therapeutically treated KPV+/+ mice with withaferin A (WFA), an agent that disrupts vimentin intermediate filaments (IFs). We show that WFA suppresses tumor growth and reduces tumor burden in the lung. Finally, luciferase-expressing KPV+/+, KPV-/-, or KPVY117L cells were implanted into the flanks of athymic mice to track cancer metastasis to the lung. In KPVY117L cells, vimentin forms oligomers called unit-length filaments but cannot assemble into mature vimentin IFs. KPV-/- and KPVY117L cells fail to metastasize, suggesting that cell-autonomous metastasis requires mature vimentin IFs. Integrative metabolomic and transcriptomic analysis reveals that KPV-/- cells upregulate genes associated with ferroptosis, an iron-dependent form of regulated cell death. KPV-/- cells have reduced glutathione peroxidase 4 (GPX4) levels, resulting in the accumulation of toxic lipid peroxides and increased ferroptosis. Together, our results demonstrate that vimentin is required for rapid tumor growth, metastasis, and protection from ferroptosis in NSCLC.

Feasibility of a Yoga Intervention for Individuals with Mild Cognitive Impairment: A Randomized Controlled Trial.

Background: Yoga is a potentially low risk intervention for cognitive impairment that combines mental and physical practice and includes instruction on breathing, stress reduction, and mindfulness meditation. Previous research documents that yoga can target modifiable risk factors for mild cognitive impairment (MCI) progression. The authors describe a randomized feasibility trial of yoga for individuals with MCI. Methods: Participants were 37 individuals with amnestic MCI who were randomly assigned to receive 12 weeks of twice-weekly yoga intervention (YI) or healthy living education (HLE) classes. Acceptability and feasibility were assessed by tracking adverse events, class attendance, and participant satisfaction. Participants completed neuropsychological and mood measures as well as measures of potential intervention mechanisms at baseline and immediately postintervention. Results: Participants in both conditions reported high levels of satisfaction and reasonable class attendance rates. Home practice rates were low. There were no adverse events deemed related to the YI. Results showed a medium effect size in favor of the YI in visuospatial skills. The yoga group also showed a large effect size indicating decline in perceived stress compared with the HLE group, whereas HLE resulted in greater reductions in depressive symptoms after the intervention (large effect size). Conclusions: Study findings indicated that the YI was safe, modestly feasible, and acceptable to older adults with MCI. The authors found preliminary evidence that yoga may improve visuospatial functioning in individuals with MCI. Results support stress reduction as a possible mechanism for the YI. Future studies should address a YI in a larger sample and include strategies to enhance engagement and home practice.

Shining the Light on the MotionWatch8 Light Sensor for Sleep and Aging Research: What Can We Measure and What Are We Missing?

BACKGROUND: Poor sleep is common among older adults at risk for dementia and may be due to circadian dysregulation. Light is the most important external stimulus to the circadian clock and bright light therapy (BLT) has been used for >20 years to help realign circadian rhythms. However, the ability of field methods (e.g., actigraphy) to accurately determine the type and intensity of light is unknown. OBJECTIVE: We examined the ability of the MotionWatch8 (MW8) light sensor to determine: 1) light versus dark, 2) electrical light versus daylight, and 3) device-based BLT versus light which was not BLT. METHODS: We tested the MW8 under 17 daily light scenarios. Light exposure data was collected for 5 minutes during each scenario. Concurrently, we measured light exposure using the LT40 Light Meter, a sensitive measure of light intensity. We then developed individual cut-points using receiver operator characteristics analyses to determine optimal MW8 cut-points for 1) light versus dark; 2) electrical light versus daylight; and 3) light from a BLT box versus light which was not BLT. Bland-Altman plots tested the precision of the MW8 compared to the LT40. RESULTS: The MW8 accurately discriminated light versus dark (>32 lux), and electrical light versus daylight (<323 lux). However, the MW8 had poor accuracy for 1) discriminating BLT from light which was not BLT; and 2) low precision compared to the LT40. CONCLUSION: The MW8 appears to be able to discern light versus dark and electrical light versus daylight; however, there remains a need for accurate field methods capable of measuring light exposure.

Navigating uncharted waters: Developing a standardized approach for evaluating and implementing biosimilar products at a comprehensive cancer center.

PURPOSE: The processes for formulary implementation and electronic health record (EHR) integration of biosimilar products at a comprehensive cancer center are described. Implications for research protocols are also discussed. SUMMARY: The existing literature focuses on practical considerations for formulary addition of biosimilar products, but there is a lack of guidance on how to implement the change, particularly within the EHR. Before building the ordering tools for biosimilars, the clinical and informatics teams should determine the role of biosimilars at the institution, identify drug-specific product characteristics that affect medication build, and characterize implications of future formulary changes or drug shortages. Leveraging an orderable record provides the ability to include logic that maps to multiple products and also allows for future implementation of changes within the medication record rather than requiring "swaps" at the treatment protocol level. The institutional review board should coordinate changes in affected research protocols and consent forms and work with principal investigators to amend protocols when necessary. Pharmacy leaders should develop processes to oversee inventory during the transition period and minimize the risk of errors. CONCLUSION: The development of a standardized approach for evaluating and implementing biosimilar products improves efficiency and collaboration among the various team members responsible for the products' integration into existing workflows, including implications for clinical research. Implementing biosimilars for agents used to treat cancer will pose new challenges and require additional considerations. Partial implementation of biosimilars continues to pose multiple challenges in the provision of patient care.

Effect of a Multimodal Lifestyle Intervention on Sleep and Cognitive Function in Older Adults with Probable Mild Cognitive Impairment and Poor Sleep: A Randomized Clinical Trial.

BACKGROUND: Poor sleep is common among older adults with mild cognitive impairment (MCI) and may contribute to further cognitive decline. Whether multimodal lifestyle intervention that combines bright light therapy (BLT), physical activity (PA), and good sleep hygiene can improve sleep in older adults with MCI and poor sleep is unknown. OBJECTIVE: To assess the effect of a multimodal lifestyle intervention on sleep in older adults with probable MCI and poor sleep. METHODS: This was a 24-week proof-of-concept randomized trial of 96 community-dwelling older adults aged 65-85 years with probable MCI (<26/30 on the Montreal Cognitive Assessment) and poor sleep (>5 on the Pittsburgh Sleep Quality Index [PSQI]). Participants were allocated to either a multimodal lifestyle intervention (INT); or 2) education + attentional control (CON). INT participants received four once-weekly general sleep hygiene education classes, followed by 20-weeks of: 1) individually-timed BLT; and 2) individually-tailored PA promotion. Our primary outcome was sleep efficiency measured using the MotionWatch8© (MW8). Secondary outcomes were MW8-measured sleep duration, fragmentation index, wake-after-sleep-onset, latency, and PSQI-measured subjective sleep quality. RESULTS: There were no significant between-group differences in MW8 measured sleep efficiency at 24-weeks (estimated mean difference [INT -CON]: 1.18%; 95% CI [-0.99, 3.34]), or any other objective-estimate of sleep. However, INT participants reported significantly better subjective sleep quality at 24-weeks (estimated mean difference: -1.39; 95% CI [-2.72, -0.06]) compared to CON. CONCLUSION: Among individuals with probable MCI and poor sleep, a multimodal lifestyle intervention improves subjective sleep quality, but not objectively estimated sleep.

Circadian regulation of membrane physiology in neural oscillators throughout the brain.

Twenty-four-hour rhythmicity in physiology and behavior are driven by changes in neurophysiological activity that vary across the light-dark and rest-activity cycle. Although this neural code is most prominent in neurons of the primary circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus, there are many other regions in the brain where region-specific function and behavioral rhythmicity may be encoded by changes in electrical properties of those neurons. In this review, we explore the existing evidence for molecular clocks and/or neurophysiological rhythms (i.e., 24 hr) in brain regions outside the SCN. In addition, we highlight the brain regions that are ripe for future investigation into the critical role of circadian rhythmicity for local oscillators. For example, the cerebellum expresses rhythmicity in over 2,000 gene transcripts, and yet we know very little about how circadian regulation drives 24-hr changes in the neural coding responsible for motor coordination. Finally, we conclude with a discussion of how our understanding of circadian regulation of electrical properties may yield insight into disease mechanisms which may lead to novel chronotherapeutic strategies in the future.

Process Development of Sj-p80: A Low-Cost Transmission-Blocking Veterinary Vaccine for Asiatic Schistosomiasis.

Asiatic schistosomiasis caused by Schistosoma japonicum is a neglected tropical disease resulting in significant morbidity to both humans and animals - particularly bovines - in endemic areas. Infection with this parasite leads to less healthy herds, causing problems in communities which rely on bovines for farming, milk and meat production. Additionally, excretion of parasite eggs in feces perpetuates the life cycle and can lead to human infection. We endeavored to develop a minimally purified, inexpensive, and effective vaccine based on the 80 kDa large subunit of the calcium activated neutral protease (calpain) from S. japonicum (Sj-p80). Here we describe the production of veterinary vaccine-grade Sj-p80 at four levels of purity and demonstrate in a pilot study that minimally purified antigen provides protection against infection in mice when paired with a low-cost veterinary adjuvant, Montanide™ ISA61 VG. Preliminary data demonstrate that the vaccine is immunogenic with robust antibody titers following immunization, and vaccination resulted in a reduction of parasite eggs being deposited in the liver (23.4-51.4%) and intestines (1.9-55.1%) depending on antigen purity as well as reducing the ability of these eggs to hatch into miracidia by up to 31.6%. We therefore present Sj-p80 as a candidate vaccine antigen for Asiatic schistosomiasis which is now primed for continued development and testing in bovines in endemic areas. A successful bovine vaccine could play a major role in reducing pathogen transmission to humans by interrupting the parasitic life cycle and improving quality of life for people living in endemic countries.

Nonclinical Toxicology and Toxicokinetic Profile of an Oral Lanthionine Synthetase C-Like 2 (LANCL2) Agonist, BT-11.

BT-11 is an orally active, gut-restricted investigational therapeutic targeting the lanthionine synthetase C-like 2 pathway with lead indications in ulcerative colitis (UC) and Crohn disease (CD), 2 manifestations of inflammatory bowel disease (IBD). In 5 mouse models of IBD, BT-11 is effective at oral doses of 8 mg/kg. BT-11 was also efficacious at nanomolar concentrations in primary human samples from patients with UC and CD. BT-11 was tested under Good Laboratory Practice conditions in 90-day repeat-dose general toxicity studies in rats and dogs, toxicokinetics, respiratory, cardiovascular and central nervous system safety pharmacology, and genotoxicity studies. Oral BT-11 did not cause any clinical signs of toxicity, biochemical or hematological changes, or macroscopic or microscopic changes to organs in 90-day repeat-dose toxicity studies in rats and dogs at doses up to 1,000 mg/kg/d. Oral BT-11 resulted in low systemic exposure in both rats (area under the curve exposure from t = 0 to t = 8 hours [AUC0-8] of 216 h × ng/mL) and dogs (650 h × ng/mL) and rapid clearance with an average half-life of 3 hours. BT-11 did not induce changes in respiratory function, electrocardiogram parameters, or behavior with single oral doses of 1,000 mg/kg/d. There was no evidence of mutagenic or genotoxic potential for BT-11 up to tested limit doses using an Ames test, chromosomal aberration assay in human peripheral blood lymphocytes, or micronucleus assay in rats. Therefore, nonclinical studies show BT-11 to be a safe and well-tolerated oral therapeutic with potential as a potent immunometabolic therapy for UC and CD with no-observed adverse effect level >1,000 mg/kg in in vivo studies.

Lifestyle behavior patterns and mortality among adults in the NHANES 1988-1994 population: A latent profile analysis.

Evidence suggests interdependent associations of individual modifiable behaviors with health outcomes. However, such interrelations have not been accounted for in previous behavior-outcome associations. We conducted latent profile analysis (LPA) on self-reported levels of alcohol consumption, restaurant dining, vitamin/mineral supplement use, physical activity (PA) and smoke exposure (first- and second-hand smoke) separately for smokers (N = 4530) and non-smokers (N = 13,421) using data from the third National Health and Nutrition Examination Survey (NHANES III) to identify subgroups with similar levels within and across behaviors. Cox-proportional hazards models were used to compare mortality rates between subgroups from cancer, cardiovascular disease (CVD) and all-causes at an average of 16.4 (±6.1) years follow-up. Five behavioral typologies were identified in non-smokers ("Moderates", "Low Risk Factors", "Restaurant Diners", "Moderate Passive Smokers" and "Heavy Passive Smokers"), and four in smokers ("Moderates", "Low Risk Factors", "Heavy Smokers" and "Physically Active"). As a group, "Moderates" had levels of each behavior that were not significantly different from at least one other group. Compared to "Moderates", in non-smokers "Restaurant Diners" had lower hazard from all-cause (hazard ratio (HR):0.84, 95% CI:0.74-0.97) and CVD (HR:0.59, 0.43-0.82) mortality, while "Low Risk Factors" had higher cancer mortality (HR:1.38,1.03-1.84). In smokers, compared to "Moderates", higher hazards for mortality were found for "Heavy Smokers" (all cause: HR:1.34, 1.12-1.60; CVD: HR:1.52, 1.04-2.23; cancer: HR:1.41 1.02-1.96) and "Low Risk Factors" (all-cause: HR:1.58, 1.14-2.17). Taken together, when restaurant dining, PA and smoking exposures are grouped together, novel predictions for mortality occur, suggesting data on multiple behaviors may be informative for risk stratification.

Buying time: a proof-of-concept randomized controlled trial to improve sleep quality and cognitive function among older adults with mild cognitive impairment.

BACKGROUND: Current evidence suggests that good quality sleep is associated with preserved cognitive function and reduced dementia risk in older adults. Sleep complaints are especially common among older adults with mild cognitive impairment (MCI), and this may contribute to their increased risk for progression to dementia. Thus, improving their sleep may be important for maintaining their cognitive health. Chronotherapy is a set of intervention strategies that can improve sleep quality through strengthening the entrainment of the biological clock to the solar light-dark cycle, and includes strategies such as (1) bright light therapy (BLT); (2) physical activity (PA); and (3) good sleep hygiene. Of these strategies, BLT is the most potent and is based on providing individualized timing to entrain circadian rhythms. Thus, a personalized chronotherapy intervention of individually timed BLT and individually tailored PA promotion, in conjunction with general sleep hygiene education may promote older adult sleep quality. We therefore aim to carry out a proof-of-concept randomized controlled trial (RCT) to examine the efficacy of such a personalized chronotherapy intervention to improve sleep quality among older adults with MCI. METHODS/DESIGN: This was a 24-week RCT of a personalized chronotherapy intervention aimed to primarily improve sleep quality as measured by the MotionWatch8©. Participants in the personalized chronotherapy group (INT) will receive four once-weekly, general sleep hygiene education classes, followed by 20 weeks of (1) individually timed BLT and (2) bi-weekly, individually tailored PA counseling phone calls in conjunction with receiving a consumer-available PA tracker-the Fitbit® Flex™. Ninety-six adults (aged 65-85 years) classified as having MCI (i.e., Mini-Mental State Exam (MMSE) ≥ 24; Montreal Cognitive Assessment (MoCA) ≤ 26; without dementia or significant functional impairment) will be randomized to either INT or a waitlist control group (CON). DISCUSSION: The results of this trial will help determine if a personalized chronotherapy intervention that includes individually timed BLT and individually tailored PA promotion, along with general sleep hygiene education can promote sleep quality among older adults at increased risk for dementia. Our results will help inform best practices for promoting sleep quality among older adults with MCI. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02926157 . Registered on 6 October 2016.

Religious Coping in Caregivers of Family Members With Dementia.

The degree of depression experienced by caregivers of individuals with dementia was examined in relation to religious coping strategies, religious practice, and spirituality in the framework of the stress and coping model. Caregivers of 191 persons with dementia completed the Religious Coping Scale, self-report measures of religious practices and spirituality, burden, and depression. There was no evidence that any religious coping strategy or religious practice moderated the relationship between caregiving stress and depression. Certain types of religious coping strategies had a direct effect on depression. Higher levels of religious coping working with God were associated with decreased depression, whereas higher levels of religious coping working through God were associated with increased depression. Higher burden, lower overall caregiver health rating, and worse reactions to memory and behavior problems were associated with higher levels of depression. Frequency of prayer and the importance of spirituality were weakly associated with lower levels of depression.

Barriers for integrating personalized medicine into clinical practice: a qualitative analysis.

Personalized medicine-tailoring interventions based on individual's genetic information-will likely change routine clinical practice in the future. Yet, how practitioners plan to apply genetic information to inform medical decision making remains unclear. We aimed to investigate physician's perception about the future role of personalized medicine, and to identify the factors that influence their decision in using genetic testing in their practice. We conducted three semi-structured focus groups in three health regions (Fraser, Vancouver coastal, and Interior) in British Columbia, Canada. In the focus groups, participants discussed four topics on personalized medicine: (i) physicians' general understanding, (ii) advantages and disadvantages, (iii) potential impact and role in future clinical practice, and (iv) perceived barriers to integrating personalized medicine into clinical practice. Approximately 36% (n = 9) of physicians self-reported that they were not familiar with the concept of personalized medicine. After introducing the concept, the majority of physicians (68%, n = 19 of 28) were interested in incorporating personalized medicine in their practice, provided they have access to the necessary knowledge and tools. Participants mostly believed that genetic developments will directly affect their practice in the future. The key concerns highlighted were physician's access to clinical guidelines and training opportunities for the use of genetic testing and data interpretation. Despite the challenges that personalized medicine can create, in general, physicians in the focus groups expressed strong interest in using genetic information in their practice if they have access to the necessary knowledge and tools.

NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteolysis.

BACKGROUND: Maintenance of healthy bone requires the balanced activities of osteoclasts (OCs), which resorb bone, and osteoblasts, which build bone. Disproportionate action of OCs is responsible for the bone loss associated with postmenopausal osteoporosis and rheumatoid arthritis. NF-κB inducing kinase (NIK) controls activation of the alternative NF-κB pathway, a critical pathway for OC differentiation. Under basal conditions, TRAF3-mediated NIK degradation prevents downstream signaling, and disruption of the NIK:TRAF3 interaction stabilizes NIK leading to constitutive activation of the alternative NF-κB pathway. METHODOLOGY/PRINCIPAL FINDINGS: Using transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), we now find that alternative NF-κB activation enhances not only OC differentiation but also OC function. Activating NT3 with either lysozyme M Cre or cathepsinK Cre causes high turnover osteoporosis with increased activity of OCs and osteoblasts. In vitro, NT3-expressing precursors form OCs more quickly and at lower doses of RANKL. When cultured on bone, they exhibit larger actin rings and increased resorptive activity. OC-specific NT3 transgenic mice also have an exaggerated osteolytic response to the serum transfer model of arthritis. CONCLUSIONS: Constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli.

Hippocampal nAChRs mediate nicotine withdrawal-related learning deficits.

Nicotine modulation of learning may contribute to its abuse liability. The role of hippocampal nicotinic acetylcholine receptors (nAChRs) in the effects of acute, chronic and withdrawal from chronic nicotine on learning was assessed via intrahippocampal drug infusion in mice. Acute dorsal hippocampal nicotine infusion enhanced contextual fear conditioning. Conversely, chronic intrahippocampal infusion of a matched dose had no effect, and withdrawal from chronic infusion impaired learning. Thus, hippocampal functional adaptation, evidenced by learning deficits during abstinence, occurs with the transition from acute to chronic nicotine exposure. To investigate which hippocampal nAChRs mediate these adaptations, C57BL/6, beta2 nAChR subunit knockout (KO), and wildtype (WT) mice treated chronically with systemic nicotine received intrahippocampal dihydro-beta-erythroidine (a high affinity nAChR antagonist). Intrahippocampal dihydro-beta-erythroidine precipitated learning deficits in all but the KO mice. Therefore, the action of nicotine at hippocampal beta2 nAChRs mediates adaptations in hippocampal function that underlie withdrawal deficits in contextual fear conditioning.

The effect of tamoxifen or exemestane on bone mineral density during the first 2 years of adjuvant treatment of postmenopausal women with early breast cancer.

BACKGROUND: Adjuvant therapy with aromatase inhibitors is associated with increased bone loss in postmenopausal women with breast cancer. We assessed changes in bone mineral density (BMD) from baseline to 24 months in patients receiving either tamoxifen (T) or exemestane (E). PATIENTS AND METHODS: A total of 578 women randomly assigned to T 20 mg per day orally or E 25 mg/day orally enrolled in this substudy; baseline, 12-month, and 24-month BMD measurements of the femur and lumbar spine by dual-energy x-ray absorptiometry were planned. Women receiving bone antiresorptive agents were excluded. Mean BMD changes from baseline to 12 and 24 months were tested between the treatment groups using 2-sample t tests and both g/cm2 (as percent changes) and T scores (as differences from baseline). RESULTS: A total of 167 women with all 3 imaging studies were evaluable and form the basis of this report (T=89, E=78). Using T scores, the mean difference from baseline was significant between the 2 groups at 12 months at both the spine (P=.0002) and the hip (P=.0004), and at 24 months only at the hip (P=.02). CONCLUSION: More bone loss occurred during the first 12 months of treatment with E compared with T, but by 2 years the differences were less apparent and bone loss with E had slowed.